tbuckley/cabot-search huggingface dataset:
Protein–protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies
Authors: Bobby Lucero, Karol R. Francisco, Lawrence J. Liu, Conor R. Caffrey, Carlo Ballatore
Journal: Trends in Pharmacological Sciences (2023)

The development of small-molecule inhibitors or stabilizers of selected protein–protein interactions (PPIs) of interest holds considerable promise for the development of research tools as well as candidate therapeutics. In this context, the covalent modification of selected residues within the target protein has emerged as a promising mechanism of action to obtain small-molecule modulators of PPIs with appropriate selectivity and duration of action. Different covalent labeling strategies are now available that can potentially allow for a rational, ground-up discovery and optimization of ligands as PPI inhibitors or stabilizers. This review article provides a synopsis of recent developments and applications of such tactics, with a particular focus on site-directed fragment tethering and proximity-enabled approaches.
Microfluidic Controllable Preparation of Iodine‐131‐Labeled Microspheres for Radioembolization Therapy of Liver Tumors
Authors: Qing‐Rong Jiang, Xing‐Qun Pu, Chuan‐Fu Deng, Wei Wang, Zhuang Liu, Rui Xie, Da‐Wei Pan, Wen‐Jie Zhang, Xiao‐Jie Ju, Liang‐Yin Chu
Journal: Advanced Healthcare Materials (2023)

Transcatheter arterial radioembolization (TARE) is of great significance for the treatment of advanced hepatocellular carcinoma (HCC). However, the existing radioembolic microspheres still have problems such as non-degradability, non-uniform size, and inability to directly monitor in vivo, which hinders the development of TARE. In this paper, a novel radioembolic agent, 131 I-labeled methacrylated gelatin microspheres (131 I-GMs), is prepared for the treatment of HCC. Water-in-oil (W/O) emulsion templates are prepared by a simple one-step microfluidic method to obtain methacrylated gelatin microspheres (GMs) after UV irradiation. A series of GMs with uniform and controllable size is obtained by adjusting the flow rate of each fluid. Both air-dried and freeze-dried GMs can quickly restore their original shape and size, and still have good monodispersity, elasticity, and biocompatibility. The radiolabeling experiments show that 131 I can efficiently bind to GMs by chloramine-T method, and the obtained 131 I-GMs have good radioactive stability in vitro. The results of in vivo TARE treatment in rats show that 131 I-GMs can be well retained in the hepatic artery and have a good inhibitory effect on the progression of liver cancer, showing the potential for the treatment of HCC.
Association of genetic risk and outcomes in patients with atrial fibrillation: interactions with early rhythm control in the EAST-AFNET4 trial
Authors: Shinwan Kany, Christoph Al-Taie, Carolina Roselli, James P Pirruccello, Katrin Borof, Carla Reinbold, Anna Suling, Linda Krause, Bruno Reissmann, Renate B Schnabel, Tanja Zeller, Antonia Zapf, Karl Wegscheider, Larissa Fabritz, Patrick T Ellinor, Paulus Kirchhof
Journal: Cardiovascular Research (2023)

The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known.Array genotyping and imputation for common genetic variants were performed. Polygenic risk scores (PRS) were calculated for AF (PRS-AF) and ischaemic stroke risk (PRS-stroke). The effects of PRS-AF and PRS-stroke on the primary outcome (composite of cardiovascular death, stroke, and hospitalization for acute coronary syndrome or worsening heart failure), its components, and recurrent AF were determined.A total of 1567 of the 2789 trial patients were analysed [793 randomized to early rhythm control; 774 to usual care, median age 71 years (65-75), 704 (44%) women]. Baseline characteristics were similar between randomized groups. Early rhythm control reduced the primary outcome compared with usual care [HR 0.67, 95% CI: (0.53, 0.84), P < 0.001]. The randomized intervention, early rhythm control, did not interact with PRS-AF (interaction P = 0.806) or PRS-stroke (interaction P = 0.765). PRS-AF was associated with recurrent AF [HR 1.08 (01.0, 1.16), P = 0.047]. PRS-stroke showed an association with the primary outcome [HR 1.13 (1.0, 1.27), P = 0.048], driven by more heart failure events [HR 1.23 (1.05-1.43), P = 0.010] without differences in stroke [HR 1.0 (0.75, 1.34), P = 0.973] in this well-anticoagulated cohort. In a replication analysis, PRS-stroke was associated with incident AF [HR 1.16 (1.14, 1.67), P < 0.001] and with incident heart failure in the UK Biobank [HR 1.08 (1.06, 1.10), P < 0.001]. The association with heart failure was weakened when excluding AF patients [HR 1.03 (1.01, 1.05), P = 0.001].Early rhythm control is effective across the spectrum of genetic AF and stroke risk. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risk and treatment.ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.
Health Insurance Coverage and Postpartum Outcomes in the US
Authors: Ian J. Saldanha, Gaelen P. Adam, Ghid Kanaan, Michael L. Zahradnik, Dale W. Steele, Kenneth K. Chen, Alex F. Peahl, Valery A. Danilack-Fekete, Alison M. Stuebe, Ethan M. Balk
Journal: JAMA Network Open (2023)

Importance Approximately half of postpartum individuals in the US do not receive any routine postpartum health care. Currently, federal Medicaid coverage for pregnant individuals lapses after the last day of the month in which the 60th postpartum day occurs, which limits longer-term postpartum care. Objective To assess whether health insurance coverage extension or improvements in access to health care are associated with postpartum health care utilization and maternal outcomes within 1 year post partum. Evidence Review Medline, Embase, CENTRAL, CINAHL, and ClinicalTrials.gov were searched for US-based studies from inception to November 16, 2022. The reference lists of relevant systematic reviews were scanned for potentially eligible studies. Risk of bias was assessed using questions from the Cochrane Risk of Bias tool and the Risk of Bias in Nonrandomized Studies of Interventions tool. Strength of evidence (SoE) was assessed using the Agency for Healthcare Research and Quality Methods Guide. Findings A total of 25 973 citations were screened and 28 mostly moderate-risk-of-bias nonrandomized studies were included (3 423 781 participants) that addressed insurance type (4 studies), policy changes that made insurance more comprehensive (13 studies), policy changes that made insurance less comprehensive (2 studies), and Medicaid expansion (9 studies). Findings with moderate SoE suggested that more comprehensive association was likely associated with greater attendance at postpartum visits. Findings with low SoE indicated a possible association between more comprehensive insurance and fewer preventable readmissions and emergency department visits. Conclusions and Relevance The findings of this systematic review suggest that evidence evaluating insurance coverage and postpartum visit attendance and unplanned care utilization is, at best, of moderate SoE. Future research should evaluate clinical outcomes associated with more comprehensive insurance coverage.
Protein@Cyanine‐Based NIR‐II Lymphography Enables the Supersensitive Visualization of Lymphedema and Tumor Lymphatic Metastasis
Authors: Jiajun Xu, Yijing Du, Tianyang Han, Ningning Zhu, Shoujun Zhu
Journal: Advanced Healthcare Materials (2023)

Visualization of the lymphatic system is clinically indispensable for the diagnosis and/or treatment of lymphatic diseases. Although indocyanine green (ICG) lymphography becomes an alternate imaging modality compared to traditional lymphoscintigraphy, it is still far from ideal due to the insufficient detection depth and low spatiotemporal resolution. Herein, protein@cyanine probes are rationally developed to solve the limitations of the current near-infrared-I (NIR-I) lymphography. The protein@cyanine probes are synthesized following a chlorine-containing dye-labeling strategy based on structure-selectivity (facile covalent binding between the dye and protein with a 1:1 molar ratio). As expected, the probes display exceptional NIR-II imaging ability with much-improved imaging contrast/resolution and controllable pharmacokinetics, superior to the clinical ICG. The protein@cyanine probes locate lymph nodes and delineate lymphatic vessels with super-high sensitivity and signal-to-background ratio, enabling real-time diagnosing lymphatic diseases such as lymphedema and tumor lymphatic metastasis. In particular, the NIR-II lymphography provides an opportunity to discover the disparate morbidity rate of primary lymphedema in different types of mice. Given the fact of lacking clinically transferable NIR-II probes, this work not only provides a promising strategy for enriching of the current library of NIR-II probes, but also promotes the clinical translation of NIR-II lymphography technology.
Biomechanical control of lymphatic vessel physiology and functions
Authors: Veronique Angeli, Hwee Ying Lim
Journal: Cellular and Molecular Immunology (2023)

Abstract The ever-growing research on lymphatic biology has clearly identified lymphatic vessels as key players that maintain human health through their functional roles in tissue fluid homeostasis, immunosurveillance, lipid metabolism and inflammation. It is therefore not surprising that the list of human diseases associated with lymphatic malfunctions has grown larger, including issues beyond lymphedema, a pathology traditionally associated with lymphatic drainage insufficiency. Thus, the discovery of factors and pathways that can promote optimal lymphatic functions may offer new therapeutic options. Accumulating evidence indicates that aside from biochemical factors, biomechanical signals also regulate lymphatic vessel expansion and functions postnatally. Here, we review how mechanical forces induced by fluid shear stress affect the behavior and functions of lymphatic vessels and the mechanisms lymphatic vessels employ to sense and transduce these mechanical cues into biological signals.
Reply: Consensus subtypes of HCC associated with clinical outcomes and genomic phenotypes
Authors: Sun Young Yim, Ju-Seog Lee
Journal: Hepatology (2023)

We thank Dr. Awan for taking an interest in our study on consensus subtypes of HCC.1 He raised interesting points of discussion about appropriate normalization of data across diverse platforms, sharing clinical data to enhance the validation and refinement of the study, evaluating the tumor purity and immune cell population in the tumor microenvironment using data deconvolution algorithms, and the potential significance of tumor mutation burden in consensus subtypes and its association with clinical outcomes. To address the issue of a batch effect in gene expression data obtained from various platforms, we utilized the MBatch algorithm (v. 1.4.1) that was developed while analyzing data from The Cancer Genome Atlas (TCGA) study.2 This algorithm is extensively used for normalizing genomic and proteomic data across multiple cancer types from the TCGA project. The MBatch algorithm can be found on GitHub (https://github.com/MD-Anderson-Bioinformatics/BatchEffectsPackage), and additional information can be accessed at https://bioinformatics.mdanderson.org/public-software/tcga-batch-effects/. We improved the clarity of our study by updating the clinical data of the validation set (GSE16757 and GSE43619). Key clinical data, such as patient's survival and tumor recurrence, are now available on the gene expression omnibus portal site (https://www.ncbi.nlm.nih.gov/geo/). In addition to estimating tumor purity according to hematoxylin and eosin staining, we used deconvoluting algorithms, such as ABSOLUTE, ESTIMATE, and CPE, to our data set and showed that tumor purity is associated with the consensus subtypes (Supplemental Figure S12). Based on assessment using CIBERSORT,3 we observed an interesting correlation between M1 macrophages, CD8 T cells, and the subtypes (Supplemental Figure S14). The final concern is the lack of in-depth analysis of the tumor mutation burden. Because mutation burden is not significantly associated with the subtype (Figure 3A), we did not investigate it further in HCC tumors. In contrast to mutation burden, we found that the chromosome instability reflected in copy number alterations is highly associated with the subtypes. Once again, we thank Dr. Awan and believe that our responses have fully addressed his concerns and will prevent any confusion among future readers.
Microarray patches for managing infections at a global scale
Authors: Qonita Kurnia Anjani, Akmal Hidayat Bin Sabri, Aaron J. Hutton, Álvaro Cárcamo-Martínez, Luki Ahmadi Hari Wardoyo, Alvanov Zpalanzani Mansoor, Ryan F. Donnelly
Journal: Journal of Controlled Release (2023)

Since the first patent for micro array patches (MAPs) was filed in the 1970s, research on utilising MAPs as a drug delivery system has progressed significantly, evidenced by the transition from the simple 'poke and patch' of solid MAPs to the development of bio responsive systems such as hydrogel-forming and dissolving MAPs. In addition to the extensive research on MAPs for improving transdermal drug delivery, there is a growing interest in using these devices to manage infectious diseases. This is due to the minimally invasive nature of this drug delivery platform which enable patients to self-administer therapeutics without the aid of healthcare professionals. This review aims to provide a critical analysis on the potential utility of MAPs in managing infectious diseases which are still endemic at a global scale. The range of diseases covered in this review include tuberculosis, skin infections, malaria, methicillin-resistant Staphylococcus aureus infections and Covid-19. These diseases exert a considerable socioeconomic burden at a global scale with their impact magnified in low- and middle-income countries (LMICs). Due to the painless and minimally invasive nature of MAPs application, this technology also provides an efficient solution not only for the delivery of therapeutics but also for the administration of vaccine and prophylactic agents that could be used in preventing the spread and outbreak of emerging infections. Furthermore, the ability of MAPs to sample and collect dermal interstitial fluid that is rich in disease-related biomarkers could also open the avenue for MAPs to be utilised as a minimally invasive biosensor for the diagnosis of infectious diseases. The efficacy of MAPs along with the current limitations of such strategies to prevent and treat these infections will be discussed. Lastly, the clinical and translational hurdles associated with MAP technologies will also be critically discussed.
Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC) Unveils New Actionable Genomic Aberrations in PACC
Authors: Vaia Florou, Andrew Elliott, Matthew H. Bailey, David Stone, Kajsa Affolter, Heloisa P. Soares, Chris Nevala-Plagemann, Courtney Scaife, Phillip Walker, W. Michael Korn, Emil Lou, Rachna T. Shroff, Peter J. Hosein, Ignacio Garrido-Laguna
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets. Experimental Design: PACC specimens (n = 51) underwent next-generation sequencing of DNA (n = 29) or whole exome (n = 22) and RNA (whole transcriptome, n = 29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC; n = 4,205). In parallel, we conducted a retrospective review of patients with PACC treated at Huntsman Cancer Institute (HCI). Results: The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared with PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the 7 patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than 3 years. Conclusions: There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.
LXR Signaling-Mediated Cholesterol Metabolism Reprogramming Regulates Cancer Cell Metastasis
Authors: Pankaj K. Singh, Kamiya Mehla
Journal: Cancer Research (2023)

Metastasis is a key contributor to mortality in patients with cancer. While many regulators of metastasis have been identified, critical targets to prevent and inhibit metastatic tumor growth remain elusive. A recent study in this issue of Cancer Research by Deng and colleagues compared gene expression signatures between primary esophageal squamous cell carcinoma tumors and metastatic tumors and combined the analysis with genes induced in metastatic cancer cell lines, which identified anoctamin 1 (ANO1) as a key driver of metastasis. ANO1 caused cholesterol accumulation by inhibiting LXR signaling and decreased cholesterol hydroxylation by downregulating the expression of cholesterol hydroxylase CYP27A1. ANO1 also regulated tumor cell-fibroblast cross-talk that contributed to inflammatory cytokine signaling (IL1β) and metastasis. Through in silico analysis, the study identified a novel small-molecule inhibitor of ANO1 that decreased tumor burden at a metastatic site. These studies provide novel insights into the role of ANO1 in cellular cholesterol metabolism and associated signaling in mediating metastasis. See related article by Deng et al., p. 1851.
Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns
Authors: Yixin Cai, Kangli Chen, Changsheng Liu, Xue Qu
Journal: Bioactive Materials (2023)

Diabetic wound is a great threat to patient's health and lives. The refractory diabetic wound shows spatial inflammation patterns, in which the early-wound pattern depicts a deprived acute inflammatory response, and the long-term non-healing wound pattern delineates an excessive and persistent inflammation due to the delayed immune cell infiltration in a positive feedback loop. In this work, we give points to some strategies to normalize the dysregulated immune process based on the spatial inflammation pattern differences in diabetic wound healing. First of all, inhibiting inflammatory response to avoid subsequent persistent and excessive immune infiltration for the early diabetic wound is proposed. However, diabetic wounds are unperceptive trauma that makes patients miss the best treatment time. Therefore, we also introduce two strategies for the long-term non-healing diabetic wound. One strategy is about changing chronic wounds to acute ones, which aims to rejuvenate M1 macrophages in diabetic wounds and make spontaneous M2 polarization possible. To activate the controllable proinflammatory response, western medicine delivers proinflammatory molecules while traditional Chinese medicine develops "wound-pus promoting granulation tissue growth theory". Another strategy to solve long-term non-healing wounds is seeking switches that target M1/M2 transition directly. These investigations draw a map that delineates strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns systematically.
Abstract A070: Determining gene expression regulated by androgen receptor variant 7 in co-loss of MAP3K7/CHD1 prostate cancer
Authors: Claire Gillette, Lauren Jillson, Scott Cramer
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the second leading cancer diagnosis in men. The ACS estimates 268,490 new cases of PCa and 34,500 deaths in 2022. Most patients with local PCa are disease free at the 5-year mark. Patients with metastatic PCa only have a 31% 5-year disease-free survival rate. While these patients may initially respond to androgen deprivation therapy, many will progress to castration-resistant prostate cancer (CRPC) and fail treatment. There is a need to develop new therapies to treat CRPC. The Cramer lab studies the dual deletion of MAP3K7 and CHD1 PCa subtype. In MAP3K7/CHD1-depleted PCa cell lines the ratio of AR splicing variants shifts to enrich for the constitutively active variant AR-v7, a known driver of CRPC. Other studies demonstrated that AR-v7 has unique target genes and can alter canonical AR target gene expression. I hypothesize that gain of AR-v7 signaling activates atypical gene targets which alter the gene expression of MAP3K7/CHD1-depleted PCa. I will determine the chromatin-binding targets and identify AR-v7 specific candidate genes. Patients with loss of MAP3K7 and CHD1 also enrich in the spliceosome protein U2AF2, therefore I will also perform transcriptomics with/without AR-FL and AR-v7 to characterize the larger impacts of AR-variant signaling at the RNA level. To this end, I will develop an inducible knockdown system in dual shMAP3K7/shCHD1 cells targeting AR-FL, AR-v7, and AR-Total. This will provide insight into the role of AR-v7 in two stages of gene expression and identify candidate therapeutic genes/pathways in loss of MAP3K7 and CHD1 PCa. Citation Format: Claire Gillette, Lauren Jillson, Scott Cramer. Determining gene expression regulated by androgen receptor variant 7 in co-loss of MAP3K7/CHD1 prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A070.
Serotyping for Homotransplantation
Authors: Ramon Patel, Max R. Mickey, Paul I. Terasaki
Journal: New England Journal of Medicine (1968)

During the past four years 104 patients who had received kidneys from either living unrelated or cadaver donors were typed and analyzed, to assess the effect of matching on endogenous creatinine clearance, rejection grades, current overall clinical status and duration of graft survival. Of those whose current survival exceeds three months, the matched group had a mean creatinine clearance of 78.5 ± 23.6 as compared with 50.1 ± 26.4 ml per minute in the mismatched group (p equal to 0.005), in which clearance tended to deteriorate after relatively long periods of comparative stability. Matched patients were also clinically superior (p equal to 0.02) and less prone to multiple or severe rejection episodes (p equal to 0.001). Although early survival was not influenced, survival was better in the matched group after the first year. Matchings on the basis of 5 HL-A antigens thus correlates with outcome of transplantation from unrelated donors, as is true in related donors.